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Epidémiologie génétique du VHB Anders Boyd, MPH, PhD Inserm U707 Hôpital Saint-Antoine Service des maladies infectieuses et tropicales Paris, France.

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Presentation on theme: "Epidémiologie génétique du VHB Anders Boyd, MPH, PhD Inserm U707 Hôpital Saint-Antoine Service des maladies infectieuses et tropicales Paris, France."— Presentation transcript:

1 Epidémiologie génétique du VHB Anders Boyd, MPH, PhD Inserm U707 Hôpital Saint-Antoine Service des maladies infectieuses et tropicales Paris, France

2 Summary Epidemiology and clinical course Genetic variability Therapeutic considerations –Virological response, failure, and suboptimal response –Therapeutic options Perspectives Conclusion

3 Top 3 most common routes of transmission Epidemiology HBVHIV Heterosexual/ Homosexual contact IDU Mother-to-child transmission Heterosexual/ Homosexual contact IDU Mother-to-child transmission

4 Global prevalence HIV prevalence, 2008 90% of HIV-infected patients with markers of prior HBV infection + 5-15% w/ chronic infection 1 HIV (33M), HBV (400M) making 2-4M HIV-HBV 2 1 Alter M. J Hepatol 2006. 2 WHO Report, 2008. Epidemiology

5 http://ocw.tufts.edu/Content/48/lecturenotes/595117/595146 Clinical course of co-infection

6 Impact on morbidity/mortality cART era Incidence/Mortality AIDS-related events 1 Liver disease morbidity/mortality 2,3 Ex: 12 382 patients living in Europe 36% excess risk / HBV 4 Acute HBV infection Adults: 25% chronic Children: 50-90% chronic ESLD & HCC 5,6 1 Palella FJ, JAIDS 2006. 2 Konopnicki D, AIDS 2005. 3 Lewden C, JAIDS 2008. 4 Nikolopoulos G, CID 2009. 5 Thio CL, Lancet 2002. 6 Salmon-Ceron D, J Hepatol 2009

7 Genetic variability Datta et al. Virology Journal, 2008 Genotypic distributions worldwide

8 Genetic variability and public health impact Chen C-F, Gastroenterology, 2011. Risk of Hepatocellular CarcinomaaHR (95%CI)p Group of long-term HBV DNA change Control group: HBV DNA level <10 4 1.00 (referent) Group A-B-C: to <10 4 2.25 (0.68–7.37)0.18 Group D: at 10 4 to 10 5 3.12 (1.09–8.89)0.03 Group E-F:/ a t 10 5 to 10 6 8.85 (3.85–20.35)<0.001 Group G-H:/ at 10 6 to 10 7 16.78 (7.33–38.39)<0.001 Group I: at >10 7 3.61 (1.15–11.38)0.03 HBV genotype B or mixed genotype1.00 (referent) C2.05 (1.20–3.51).009 Adjusted for age, sex, cigarette smoking, alcohol drinking, total number of repeated measurements of ALT, long-term pattern of ALT, and the other factors listed in the table.

9 Genetic variability and public health impact pol mutations selected by exposure to nucleos(t)ides (3TC, FTC, ADV, ETV, LdT) Double stranded DNA with overlapping reading frames: pol mutations S mutations S mutations selected as consequence of pol mutations + selective pressure of host origin associated with decrease of HBs antigenicity 1 and vaccine escape 2 false negative with ELISA test Lee WM.N Engl J Med. 1997 1 Torresi J, J Clinc Virol 2002. 2 Kamili S, Hepatol 2009.

10 Virological response Definition of virological response on nucleoside analogue (NA) therapy: –"Virological response is defined as undetectable HBV DNA by a sensitive PCR assay [usually at W48]. –It is usually evaluated every 3-6 months during therapy depending on the severity of liver disease and the type of NA. EASL Clinical Practice Guidelines, April 2012

11 Virological failure Primary antiviral resistance mutations in the polymerase gene TreatmentDomainNumber of mutations BCDE LAM/TdVrtV173L rtL180M rtA181T/V rtM204V/I1 ADVrtA181T/VrtN236T1 TDFrtA181T/V (rtA194T) rtN236T? ETVrtL180M rtT184 rtM204I/V rtS202 rtM250I/V3 Gish R et al., Lancet Inf Dis, 2012

12 Suboptimal response 0.00 0.20 0.40 0.60 0.80 1.00 Cumulative probability 012243648607284 Time from TDF-initiation (months) Lacombe et al., CROI 2009; Unpublished data, French HIV-HBV and BI-LIVER cohorts 23.5%4.3% Delayed response is commonplace in HIV-HBV co- infected patients Cumulative probability in achieving undetectable HBV in HIV- HBV co-infected patients treated with TDF

13 Determinants of suboptimal response Virological determinants in delayed response LAMTDF+FTC Early virological response (<2.3 log 10 IU/mL) (n=32) Primary non response (n=14) Delayed response (n=7) Non-adherent (n=7) 6 MO END FU Lada O et al., Liver Int, 2012; Lada O et al. Antiviral Ther, 2012. In the DR vs EVR group: - Higher % of HBV genotype G - Longer duration of LAM - Higher % of mutated HBV clones (quasispecies variability)

14 Therapeutic options Intensification No modificationSwitch Suboptimal response What is the effect of these treatment options on genetic variability? EASL Clinical Practice Guidelines, April 2012

15 Therapeutic options Intensification: evidence that anti-HBV drugs with lower potency may not work Treatment effectiveness: LAM 97%, TDF 98%, LAM+TDF 97% Median HBV virion half-life: 1.2 days (IQR: 0.5-1.4 days) Median infected cell half-life: 7.9 days (6.3-11.0 days) Matthews Avihingsanon et al. Hepatol 2008; Lewin et al. Hepatol, 2009

16 Therapeutic options Intensification: evidence that anti-HBV drugs with lower potency may work OR95% CI HBV active therapy TDF+FTC/LAM1.00 No TDF/LAM/FTC16.8(4.1-69.0) LAM/FTC only36.6(7.2-186.0) TDF only8.4(1.3-54.0) Detectable HIV virus7.4(2.4-22.3) HBeAg+85.2(18.2-398.6) Matthews et al. AIDS 2009 Ordinal regression ( 6.3 log 10 IU/mL)

17 Therapeutic options Switching to less potent therapies: evidence of its effect on HBV parameters Unpublished data, French HIV-HBV and BI-LIVER Cohorts

18 Therapeutic options Effect of multiple switching on genetic variability in LAM- experienced, HIV-HBV co-infected patients % of patients with incident mutations TDF±LAM/FTC Multiple switches Mutation class% (n) Alkyl phosphonate-associated pol-gene(n=49)(n=15) 6.16.7 Immune-associated S-gene(n=73)(n=18) 1.45.6 L-nucleoside-associated pol- gene/antiviral-associated S-gene (n=64)(n=15) 9.433.3 Lacombe et al., Hepatology, 2012 [accepted]

19 Perspectives Supériorité entre les traitements anti-VHB chez les patients co-infectés par le VIH et VHB ? Dans le contexte africain ? EfficaceNon efficace Suppression de la réplication virale Mutations de résistance Perte (décroissance) de lag HBe/HBs morbidité/mortalité risque des mutations liées à lantigène HBs TDF > 3TC ?? TDF > 3TC ??

20 Perspectives VarBVa : étude de cohorte, nichée, prospective ARV ITP fixe TDF+FTC OMSOMS +INH ARV précoce +INH ARV précoce ARV ITP adapté ARV continue TRIVACAN TEMPRANO 3TC Sans tx Critères dinclusion –Sérologie VIH-1 positive ou VIH-1+VIH-2 positive –HBsAg+ ( 6 mois) –Naïf de traitement Sans ARV

21 Conclusion Suboptimal response is common in HIV-HBV co- infected patients –Most patients can achieve undetectable HBV-DNA –Transient replication can occur Many genetic determinants of treatment response are up for debate – especially in treatment-naïve patients and in the African context Impact of suboptimal response in HIV-HBV co- infection on clinical outcomes is largely unknown

22 Hospital Saint-Antoine, Paris:Hospital Tenon, Paris: N. Algans M. Atlou C. Bessette H. Bideault D. Binet D. Bollens E. Bui F. Cao A. Charrois N. Desplanque G. Epinette L. Fonquernie J. Guéchot N. Harchi J. L. Lagneau F. Lallemand B. Lefebvre C. Lupin V. Massari C. Masseguin O. Massot J. L. Meynard M. C. Meyohas R. Mouchotte L. Morand-Joubert H. Rougier M. Sebire L. Serfaty P. Tran P. Tangre J. Tredup D. Wendum X. Amiot A. Baakili F. Bani-Sadr P. Callard B. Cardon E. Chakvetadze B. Fouqueray S. Gharakhanian J. D. Grange J. B. Guiard-Schmid B. Hadacek M. G. Lebrette Ph. Mariot R. Missonnier C. Le Pendeven G. Pialoux C. Poirot W. Rozenbaum L. Slama M. P. Treilhou J. P. Vincensini F. Zatla C. Zurita Hospital Saint-Louis, Paris:Hospital Hôtel-Dieu, Lyon: Laboratoire du Chemin-Vert: P. Bertheau N. de Castro N. C. de Verdière J. Delgado S. Ferret S. Fournier I. François A. Furco A. Janin M. Lafaurie M. Lagrange S. Neuville P. Palmer J. Pavie C. Pintado D. Ponscarme A. Raschline C. Scieux M. E. Schlageter D. Séréni O. Tauléra M. Tourneur F. Vincent C. Augustin-Normand F. Bailly I. Bordes C. Brochier M. Chevallier L. Cotte V. Guéripel B. Lebouche M. Maynard-Muet I. Schlienger V. Thoirain A. M. Trabaud C. Trepo A. Ollivet C. Durrafour F. Lavocat F. Zoulim G. Kreplak R. Legouge Inserm U707: G. Pannetier F. Carrat Gilead Sciences, Inc.


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